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Pandya-Jones, Amy; Markaki, Yolanda; Serizay, Jacques; Chitiashvili, Tsotne; Leon, Walter R. Mancia; Damianov, Andrey; Chronis, Constantinos; Papp, Bernadett; Chen, Chun-Kan; McKee, Robin; Wang, Xiao-Jun; Chau, Anthony; Sabri, Shan; Leonhardt, Heinrich; Zheng, Sika; Guttman, Mitchell; Black, Douglas L. and Plath, Kathrin (2020): A protein assembly mediates Xist localization and gene silencing. In: Nature, Vol. 587, No. 7832: pp. 145-151

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Nuclear compartments have diverse roles in regulating gene expression, yet the molecular forces and components that drive compartment formation remain largely unclear(1). The long non-coding RNAXistestablishes an intra-chromosomal compartment by localizing at a high concentration in a territory spatially close to its transcription locus(2)and binding diverse proteins(3-5)to achieve X-chromosome inactivation (XCI)(6,7). The XCI process therefore serves as a paradigm for understanding how RNA-mediated recruitment of various proteins induces a functional compartment. The properties of the inactive X (Xi)-compartment are known to change over time, because after initialXistspreading and transcriptional shutoff a state is reached in which gene silencing remains stable even ifXistis turned off(8). Here we show that theXistRNA-binding proteins PTBP1(9), MATR3(10), TDP-43(11)and CELF1(12)assemble on the multivalent E-repeat element ofXist(7)and, via self-aggregation and heterotypic protein-protein interactions, form a condensate(1)in the Xi. This condensate is required for gene silencing and for the anchoring ofXistto the Xi territory, and can be sustained in the absence ofXist. Notably, these E-repeat-binding proteins become essential coincident with transition to theXist-independent XCI phase(8), indicating that the condensate seeded by the E-repeat underlies the developmental switch fromXist-dependence toXist-independence. Taken together, our data show thatXistforms the Xi compartment by seeding a heteromeric condensate that consists of ubiquitous RNA-binding proteins, revealing an unanticipated mechanism for heritable gene silencing. A protein condensate formed by multivalent interactions between the long non-coding RNA Xist and specific RNA-binding proteins drives the compartmentalization required to perpetuate gene silencing on the inactive X chromosome.

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